rs267608188

Variant names:

• chr8-76983340-CAAGTA-C
• rs267608188
• NM_000318.3:c.834_838delTACTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000318.3(PEX2):​c.834_838delTACTT​(p.Phe278LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX2 NM_000318.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.73

Genes affected

PEX2 (HGNC:9717): (peroxisomal biogenesis factor 2) This gene encodes an integral peroxisomal membrane protein required for peroxisome biogenesis. The protein is thought to be involved in peroxisomal matrix protein import. Mutations in this gene result in one form of Zellweger syndrome and infantile Refsum disease. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0915 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-76983340-CAAGTA-C is Pathogenic according to our data. Variant chr8-76983340-CAAGTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX2	NM_000318.3	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 4 of 4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 3 of 3		NP_001073336.2
PEX2	NM_001172086.2	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 5 of 5		NP_001165557.2
PEX2	NM_001172087.2	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 3 of 3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 4 of 4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 3 of 3	1		ENSP00000428638.1
PEX2	ENST00000520103.5	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift_variant	Exon 3 of 3	2		ENSP00000428590.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger) Pathogenic:2

Mar 21, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 5B Pathogenic:1

Aug 16, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608188; hg19: chr8-77895576;